Hypoxic-ischemic encephalopathy is an important cause of neurologic sequalae in sick term and preterm infants during the neonatal period. Although the pathogenesis of neonatal hypoxic-ischemic encephalopathy is unclear, it has become apparent that systemic hypotension plays a central role. This is supported by a recent investigation demonstrating that energy balance is preserved in the perinatal brain during severe hypoxemia unless complicated by superimposed ischemia. The effects of ischemia on the newborn central nervous system has received little attention. Thus, the objectives of this proposal are: 1) to examine cerebral substrate delivery and uptake, tissue levels of phosphorus containing metabolites and intracellular pH before, during and following ischemia, 2) to determine cerebral vascular responsiveness to vasodilatory stimuli (hypercapnia and hypotension) following prior transient cerebral ischemia and 3) to determine if the sympathetic nervous system regulates regional brain blood flow patterns during cerebral ischemia. These studies will be performed in the piglet, an animal model whose central nervous system maturation approximates that of a near-term human infant. Organ blood flow and cardiac output will be measured using radioactive-labeled microspheres. Simultaneous sampling of arterial and cerebral venous blood will be utilized to examine cerebral handling of 02, glucose, lactic acid and ketone bodies. Nuclear magnetic resonance spectroscopy will be used to determine cerebral metabolic state. An understanding of the pathophysiology during cerebral ischemia may ultimately contribute to effective treatment rationales which at present are limited to supportive care.